Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer

Phase 3

Completed

• Conditions: Breast Adenocarcinoma; Stage IA Breast Cancer AJCC v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage IIIA Breast Cancer AJCC v7; HER2 Positive Breast Carcinoma; Stage IB Breast Cancer AJCC v7; Stage IIA Breast Cancer AJCC v6 and v7
• Interventions: Drug: Aromatase Inhibition Therapy; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel; Drug: Tamoxifen Citrate; Biological: Trastuzumab

• Registration Number: NCT00005970
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and trastuzumab to see how well they work compared to combination chemotherapy alone in treating women with breast cancer that is human epidermal growth factor receptor 2 (HER2)-positive and has spread to the lymph nodes or high-risk and has not spread to the lymph nodes. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without trastuzumab in treating breast cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To compare the combination of doxorubicin hydrochloride and cyclophosphamide (AC) followed by weekly paclitaxel with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of disease free survival (DFS). (Stage I) II. To compare the combination of AC followed by weekly paclitaxel with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of the rate of cardiac events. (Stage I) III. To compare the combination AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of DFS. (Stage II) IV. To compare the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of DFS. (Stage II) V. To compare the combination AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of the rate of cardiac events. (Stage II)

SECONDARY OBJECTIVES:

I. To compare the combination of AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of overall survival (OS).

II. To compare the combination AC followed by weekly paclitaxel with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of OS.

III. To compare the sequential schedule of the combination AC, weekly paclitaxel, and trastuzumab with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of OS.

TERTIARY OBJECTIVES:

I. To determine whether higher levels of shed ECD (extracellular domain) or autoantibodies to human epidermal growth factor receptor (HER)-2 and HER-1 measured in the serum prior to treatment are prognostic for DFS and survival.

II. To determine the concordance of central review of HER-2 overexpression as measured by the HercepTest (DAKO) and Vysis fluorescence in situ hybridization (FISH).

III. For each treatment arm, levels of brain natriuretic peptide (BNP), troponin-T (TnT), troponin-I (cTnI), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6), CD40 ligand, and troponin levels will be compared and contrasted.

IV. To determine whether genetic markers are prognostic for cardiac adverse events associated with treatment.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I\*: Patients receive doxorubicin hydrochloride intravenously (IV) and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients who completed paclitaxel on or after October 25, 2004 may receive trastuzumab for a maximum of 52 weeks either concurrently with paclitaxel or following completion of paclitaxel treatment.

ARM II\*: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients who completed paclitaxel on or after October 25, 2004 may receive trastuzumab for a maximum of 52 weeks either concurrently with paclitaxel or following completion of paclitaxel treatment.

ARM III: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity.

Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal estrogen receptor (ER)- or progesterone receptor (PR)-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually for 15 years or until disease progression.

Study Timeline

• Study Start: 2000-05-19
• Study First Submitted: 2000-07-05
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2005-04-25
• Study Completion: 2010-01-27
• Status Verified: 2020-08
• Last Update Submitted: 2020-08-13
• Last Update Posted: 2020-08-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 3436

Inclusion Criteria

• Required tumor parameters for node positive disease: NOTE: This study will continue to use the American Joint Committee on Cancer (AJCC) 5th edition for TNM classification and staging

  • Operable, histologically confirmed adenocarcinoma of the female breast and positive lymph nodes

    • Node positivity may be determined by either an axillary node dissection or a positive sentinel node finding by hematoxylin and eosin (H&E)

      • NOTE: Positive nodes refers to H&E visible nodal metastases; immunohistochemistry (IHC) positive only cells in lymph nodes will not be considered positive nodes

    • One or more positive lymph nodes whose tumors are T1-3, pN1-2, M0 are eligible

    • cN2 disease is not eligible

    • pN2 disease is eligible

    • One positive lymph node by sentinel node biopsy or at least 6 axillary nodes must be examined on axillary node dissection with at least one positive lymph node

    • Metaplastic carcinoma is eligible

  • ER/PgR determination

  • HER-2 positive (pre-entry requirement for registration)

    • FISH must show gene amplification OR

    • IHC assay must show a strong positive (3+) staining score

      • NOTE: ductal carcinoma in situ (DCIS) components should not be counted in the determination of degree of IHC staining or FISH amplification

• Required tumor parameters for high-risk node-negative disease; NOTE: This study will continue to use the AJCC 5th edition for TNM classification and staging

  • Operable, histologically confirmed adenocarcinoma of the female breast and negative lymph nodes

    • Node status may be determined by either axillary node dissection or sentinel node biopsy with H&E staining; to be considered node negative, either of the following must be true: 1) negative sentinel node biopsy or 2) no positive lymph nodes found among at least 6 axillary nodes examined on axillary node dissection
    • NOTE: IHC positive only cells in lymph nodes will not be considered positive nodes
    • Tumors > 2.0 cm (irrespective of hormonal receptor status) or > 1.0 cm if ER-negative and PR-negative disease

  • ER/PgR determination

  • HER-2 positive (pre-entry requirement for registration)

    • FISH must show gene amplification OR

    • IHC assay must show a strong positive (3+) staining score

      • NOTE: DCIS components should not be counted in the determination of degree of IHC staining or FISH amplification

• =< 84 days from mastectomy or =< 84 days from axillary dissection or sentinel node detection if the patient's most extensive breast surgery was a breast sparing procedure; (This timing is per a decision by the Breast Intergroup)

• Surgical resection margins. All tumor should be removed by either a modified radical mastectomy or a segmental mastectomy with axillary node dissection

  • Mastectomy: There will be no evidence of gross or microscopic tumor (invasive or DCIS) at the surgical resection margins noted in the final surgery or pathology reports; patients with close margins are eligible
  • Segmental mastectomy (lumpectomy): Margins must be clear of invasive cancer and DCIS
  • Axillary dissection or sentinel node dissection: There will be no gross residual adenopathy

• TAM therapy

  • May have received up to four weeks of TAM therapy, or any other hormonal agent, for this malignancy
  • May have received TAM or raloxifene for purposes of chemoprevention (e.g., Breast Cancer Prevention Trial) or for other indications (including previous breast cancer if lobular carcinoma in situ [LCIS]) but must be discontinued before registration on this study
  • May never have received TAM, raloxifene, or any other hormonal agent

• Absolute neutrophil count (ANC) >= 1500/mm^3

• Platelets (PLT) >= 100,000/mm^3

• Total bilirubin =< 1.5 x upper normal limit (UNL)

• Aspartate aminotransferase (AST) =< 2.0 x UNL

• Left ventricular ejection fraction (LVEF) within institutional normal range; if LVEF is > 75%, the investigator should consider performing a second review of the multigated acquisition (MUGA)/echocardiogram or performing a repeat MUGA/echocardiogram prior to registration; such re-reviews or repeat MUGA/echocardiogram are not permitted after registration

• Willingness to discontinue sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc., prior to registration and while on study

• Willingness to discontinue any hormonal agent such as raloxifene (Evista) prior to registration and while on study

• Non-breast malignancies that have not recurred within the last 5 years and are deemed to be at low risk for recurrence

EXCEPTIONS: These non-breast malignancies are eligible even if diagnosed =< 5 years prior to registration:

• Squamous or basal cell carcinoma of the skin that has been effectively treated

• Carcinoma in situ of the cervix that has been treated by surgery only

• Lobular carcinoma in situ (LCIS) of the ipsilateral or contralateral breast treated by surgery and/or tamoxifen only

  • Patients undergoing breast conservation therapy (i.e., lumpectomy and axillary dissection) must have plans to receive radiation therapy to the breast +/- regional lymphatics following completion of the chemotherapy; for patients treated with mastectomy, the use of radiation therapy is required for 4 or more positive lymph nodes and must be started after completion of chemotherapy; the use of radiation therapy is at the discretion of the investigator for 0-3 positive lymph nodes but, if used, must be started after the completion of chemotherapy
  • Prior to registration, the physician must designate if it is planned for the patient to receive radiation therapy (for adjuvant radiation therapy post-mastectomy or, less commonly, post-conservative therapy but not primary breast radiation as part of breast conserving treatment)
  • Willing and able to sign an informed consent
  • Gene amplified by FISH or strong positivity (3+) by HercepTest on central review; Note: The patient registers based on community HER-2 testing using FISH or IHC, AC chemotherapy is initiated; the tumor block or slides must be received =< 2 weeks from time of registration to the North Central Cancer Treatment Group (NCCTG) Operations Office for central HER-2 testing

Exclusion Criteria

• Any of the following:

  • Pregnant women
  • Nursing women
  • Women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception (condoms, diaphragm, intrauterine device [IUD], surgical sterilization, or abstinence, etc.); hormonal birth control methods are not permitted

• Locally advanced tumors (classification T4) at diagnosis including tumors fixed to chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge)

• Prior history of breast cancer, except LCIS

• Bilateral invasive carcinoma, either metachronous or synchronous (EXCEPTION: Patients diagnosed with unilateral invasive carcinoma and metachronous or synchronous DCIS of the contralateral breast treated with mastectomy are eligible)

• Prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer

• Active, unresolved infection

• Active cardiac disease

  • Any prior myocardial infarction
  • History of documented congestive heart failure (CHF)
  • Current use of digitalis or beta-blockers for CHF
  • Any prior history of arrhythmia or cardiac valvular disease requiring medications or clinically significant
  • Current use of medications for treatment of arrhythmias or angina pectoris
  • Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg)
  • Clinically significant pericardial effusion

• Prior anthracycline or taxane therapy for any malignancy

• Sensitivity to benzyl alcohol

• Neurology/Neuropathy-Sensory >= grade 2 per the National Cancer Institute's (NCI's) Common Toxicity Criteria Version 2.0; EXCEPTION: Any chronic neurologic disorder will be looked at on a case-by-case basis by the study chair

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (AC, paclitaxel, tamoxifen, aromatase inhibitor)	Tamoxifen Citrate	Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm II (AC, paclitaxel, trastuzumab, tamoxifen)	Tamoxifen Citrate	Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm III (AC, paclitaxel, trastuzumab, tamoxifen)	Tamoxifen Citrate	Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm I (AC, paclitaxel, tamoxifen, aromatase inhibitor)	Aromatase Inhibition Therapy	Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm I (AC, paclitaxel, tamoxifen, aromatase inhibitor)	Laboratory Biomarker Analysis	Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm II (AC, paclitaxel, trastuzumab, tamoxifen)	Aromatase Inhibition Therapy	Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm II (AC, paclitaxel, trastuzumab, tamoxifen)	Laboratory Biomarker Analysis	Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm II (AC, paclitaxel, trastuzumab, tamoxifen)	Trastuzumab	Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm III (AC, paclitaxel, trastuzumab, tamoxifen)	Aromatase Inhibition Therapy	Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm III (AC, paclitaxel, trastuzumab, tamoxifen)	Laboratory Biomarker Analysis	Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm III (AC, paclitaxel, trastuzumab, tamoxifen)	Trastuzumab	Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm I (AC, paclitaxel, tamoxifen, aromatase inhibitor)	Doxorubicin Hydrochloride	Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm I (AC, paclitaxel, tamoxifen, aromatase inhibitor)	Cyclophosphamide	Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm I (AC, paclitaxel, tamoxifen, aromatase inhibitor)	Paclitaxel	Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm II (AC, paclitaxel, trastuzumab, tamoxifen)	Paclitaxel	Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm II (AC, paclitaxel, trastuzumab, tamoxifen)	Cyclophosphamide	Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm II (AC, paclitaxel, trastuzumab, tamoxifen)	Doxorubicin Hydrochloride	Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm III (AC, paclitaxel, trastuzumab, tamoxifen)	Cyclophosphamide	Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm III (AC, paclitaxel, trastuzumab, tamoxifen)	Doxorubicin Hydrochloride	Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Arm III (AC, paclitaxel, trastuzumab, tamoxifen)	Paclitaxel	Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.

Primary Outcome Measures

Name	Time	Method
Duration of DFS	Time from registration to first adverse event, assessed up to 15 years	Will be estimated using the Kaplan-Meier method. A stratified log-rank test will be used to assess whether DFS differs with respect to the addition of trastuzumab to a chemotherapy regimen including AC and paclitaxel. Ninety-five percent confidence intervals will be reported for relative risks, for DFS at the 5-year point, and for absolute benefit as defined by differences in DFS and OS.

Secondary Outcome Measures

Name	Time	Method
Overall survival	Time from registration to death due to any cause, assessed up to 15 years	Will be estimated using the Kaplan-Meier method. A stratified log-rank test will be used to assess whether OS differs with respect to the addition of trastuzumab to a chemotherapy regimen including AC and paclitaxel. Ninety-five percent confidence intervals will be reported for relative risks, for OS at the 5-year point, and for absolute benefit as defined by differences in DFS and OS.

Trial Locations

Locations (157)

University of Pennsylvania/Abramson Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

University of Vermont and State Agricultural College; 🇺🇸 Burlington, Vermont, United States

The Angeles Clinic and Research Institute - Santa Monica Office; 🇺🇸 Santa Monica, California, United States

USC / Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

Ohio State University Comprehensive Cancer Center; 🇺🇸 Columbus, Ohio, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Rush University Medical Center; 🇺🇸 Chicago, Illinois, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

Massachusetts General Hospital Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Boston Medical Center; 🇺🇸 Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Kaiser Permanente Washington; 🇺🇸 Seattle, Washington, United States

University of Mississippi Medical Center; 🇺🇸 Jackson, Mississippi, United States

North Shore University Hospital; 🇺🇸 Manhasset, New York, United States

University Medical Center of Southern Nevada; 🇺🇸 Las Vegas, Nevada, United States

University of California San Diego; 🇺🇸 San Diego, California, United States

Naval Medical Center -San Diego; 🇺🇸 San Diego, California, United States

University of Minnesota/Masonic Cancer Center; 🇺🇸 Minneapolis, Minnesota, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

Mayo Clinic in Arizona; 🇺🇸 Scottsdale, Arizona, United States

Washington Hospital; 🇺🇸 Fremont, California, United States

Emory University Hospital/Winship Cancer Institute; 🇺🇸 Atlanta, Georgia, United States

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, United States

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

Stanford Cancer Institute Palo Alto; 🇺🇸 Palo Alto, California, United States

UC Irvine Health/Chao Family Comprehensive Cancer Center; 🇺🇸 Orange, California, United States

Community Cancer Institute; 🇺🇸 Clovis, California, United States

University of Arkansas for Medical Sciences; 🇺🇸 Little Rock, Arkansas, United States

Glendale Memorial Hospital and Health Center; 🇺🇸 Glendale, California, United States

Ascension Providence Hospitals - Southfield; 🇺🇸 Southfield, Michigan, United States

Dartmouth Hitchcock Medical Center; 🇺🇸 Lebanon, New Hampshire, United States

Iowa-Wide Oncology Research Coalition NCORP; 🇺🇸 Des Moines, Iowa, United States

Milford Regional Medical Center; 🇺🇸 Milford, Massachusetts, United States

Cotton O'Neil Cancer Center / Stormont Vail Health; 🇺🇸 Topeka, Kansas, United States

Tulane University Health Sciences Center; 🇺🇸 New Orleans, Louisiana, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Loyola University Medical Center; 🇺🇸 Maywood, Illinois, United States

Carle Cancer Center; 🇺🇸 Urbana, Illinois, United States

University of Maryland/Greenebaum Cancer Center; 🇺🇸 Baltimore, Maryland, United States

University of Illinois; 🇺🇸 Chicago, Illinois, United States

Northern Indiana Cancer Research Consortium; 🇺🇸 South Bend, Indiana, United States

Kansas City NCI Community Oncology Research Program; 🇺🇸 Prairie Village, Kansas, United States

Wichita NCI Community Oncology Research Program; 🇺🇸 Wichita, Kansas, United States

CHI Health Good Samaritan; 🇺🇸 Kearney, Nebraska, United States

Long Island Jewish Medical Center; 🇺🇸 New Hyde Park, New York, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone; 🇺🇸 New York, New York, United States

Englewood Hospital and Medical Center; 🇺🇸 Englewood, New Jersey, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

University of Iowa/Holden Comprehensive Cancer Center; 🇺🇸 Iowa City, Iowa, United States

Saint Francis Hospital and Medical Center - Topeka; 🇺🇸 Topeka, Kansas, United States

New Hampshire Oncology Hematology PA-Hooksett; 🇺🇸 Hooksett, New Hampshire, United States

University of Massachusetts Medical School; 🇺🇸 Worcester, Massachusetts, United States

Essentia Health Cancer Center; 🇺🇸 Duluth, Minnesota, United States

Cancer Research Consortium of West Michigan NCORP; 🇺🇸 Grand Rapids, Michigan, United States

Coborn Cancer Center at Saint Cloud Hospital; 🇺🇸 Saint Cloud, Minnesota, United States

Metro Minnesota Community Oncology Research Consortium; 🇺🇸 Saint Louis Park, Minnesota, United States

Cancer Research for the Ozarks NCORP; 🇺🇸 Springfield, Missouri, United States

Washington University - Jewish; 🇺🇸 Saint Louis, Missouri, United States

Altru Cancer Center; 🇺🇸 Grand Forks, North Dakota, United States

University of Cincinnati/Barrett Cancer Center; 🇺🇸 Cincinnati, Ohio, United States

Virginia Mason Medical Center; 🇺🇸 Seattle, Washington, United States

University of Texas Health Science Center at San Antonio; 🇺🇸 San Antonio, Texas, United States

Sanford NCI Community Oncology Research Program of the North Central Plains; 🇺🇸 Sioux Falls, South Dakota, United States

UCSF Medical Center-Mount Zion; 🇺🇸 San Francisco, California, United States

Huntsman Cancer Institute/University of Utah; 🇺🇸 Salt Lake City, Utah, United States

University of Alabama at Birmingham Cancer Center; 🇺🇸 Birmingham, Alabama, United States

Western Regional CCOP; 🇺🇸 Phoenix, Arizona, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Henry Ford Hospital; 🇺🇸 Detroit, Michigan, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Providence Portland Medical Center; 🇺🇸 Portland, Oregon, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Saint Louis-Cape Girardeau CCOP; 🇺🇸 Saint Louis, Missouri, United States

Novant Health Forsyth Medical Center; 🇺🇸 Winston-Salem, North Carolina, United States

Wake Forest University Health Sciences; 🇺🇸 Winston-Salem, North Carolina, United States

Southeast Clinical Oncology Research (SCOR) Consortium NCORP; 🇺🇸 Winston-Salem, North Carolina, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

Ochsner Medical Center Jefferson; 🇺🇸 New Orleans, Louisiana, United States

Siouxland Regional Cancer Center; 🇺🇸 Sioux City, Iowa, United States

Salina Regional Health Center; 🇺🇸 Salina, Kansas, United States

Louisiana State University Health Sciences Center Shreveport; 🇺🇸 Shreveport, Louisiana, United States

Saint Vincent Hospital/Reliant Medical Group; 🇺🇸 Worcester, Massachusetts, United States

University of Colorado Hospital; 🇺🇸 Aurora, Colorado, United States

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

Walter Reed National Military Medical Center; 🇺🇸 Bethesda, Maryland, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

Memorial Medical Center; 🇺🇸 Modesto, California, United States

Community Hospital of Monterey Peninsula; 🇺🇸 Monterey, California, United States

Salinas Valley Memorial; 🇺🇸 Salinas, California, United States

Santa Rosa Memorial Hospital; 🇺🇸 Santa Rosa, California, United States

MedStar Georgetown University Hospital; 🇺🇸 Washington, District of Columbia, United States

Mayo Clinic in Florida; 🇺🇸 Jacksonville, Florida, United States

Atlanta Regional CCOP; 🇺🇸 Atlanta, Georgia, United States

Memorial Health University Medical Center; 🇺🇸 Savannah, Georgia, United States

Northeast Georgia Medical Center-Gainesville; 🇺🇸 Gainesville, Georgia, United States

University of Hawaii Cancer Center; 🇺🇸 Honolulu, Hawaii, United States

Heartland Cancer Research NCORP; 🇺🇸 Decatur, Illinois, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Indiana University/Melvin and Bren Simon Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

Via Christi Hospital-Pittsburg; 🇺🇸 Pittsburg, Kansas, United States

Kalamazoo Center for Medical Studies; 🇺🇸 Kalamazoo, Michigan, United States

University of Missouri - Ellis Fischel; 🇺🇸 Columbia, Missouri, United States

Missouri Baptist Medical Center; 🇺🇸 Saint Louis, Missouri, United States

Montana Cancer Consortium NCORP; 🇺🇸 Billings, Montana, United States

Missouri Valley Cancer Consortium; 🇺🇸 Omaha, Nebraska, United States

Rutgers Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

Montefiore Medical Center-Weiler Hospital; 🇺🇸 Bronx, New York, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Mount Sinai Hospital; 🇺🇸 New York, New York, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

SUNY Upstate Medical Center-Community Campus; 🇺🇸 Syracuse, New York, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center; 🇺🇸 New York, New York, United States

NYP/Weill Cornell Medical Center; 🇺🇸 New York, New York, United States

State University of New York Upstate Medical University; 🇺🇸 Syracuse, New York, United States

Mission Hospital Inc-Memorial Campus; 🇺🇸 Asheville, North Carolina, United States

Cone Health Cancer Center; 🇺🇸 Greensboro, North Carolina, United States

Wilson Medical Center; 🇺🇸 Wilson, North Carolina, United States

Sanford Broadway Medical Center; 🇺🇸 Fargo, North Dakota, United States

Sanford Bismarck Medical Center; 🇺🇸 Bismarck, North Dakota, United States

Toledo Community Hospital Oncology Program CCOP; 🇺🇸 Toledo, Ohio, United States

Geisinger Medical Center; 🇺🇸 Danville, Pennsylvania, United States

Penn State Milton S Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

West Penn Hospital; 🇺🇸 Pittsburgh, Pennsylvania, United States

University of Pittsburgh Cancer Institute (UPCI); 🇺🇸 Pittsburgh, Pennsylvania, United States

Fox Chase Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Lankenau Medical Center; 🇺🇸 Wynnewood, Pennsylvania, United States

Case Western Reserve University; 🇺🇸 Cleveland, Ohio, United States

Rapid City Regional Hospital; 🇺🇸 Rapid City, South Dakota, United States

Wellmont Holston Valley Hospital and Medical Center; 🇺🇸 Kingsport, Tennessee, United States

Thompson Cancer Survival Center; 🇺🇸 Knoxville, Tennessee, United States

University of Tennessee - Knoxville; 🇺🇸 Knoxville, Tennessee, United States

University of Tennessee Health Science Center; 🇺🇸 Memphis, Tennessee, United States

Vanderbilt University/Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

Brooke Army Medical Center; 🇺🇸 Fort Sam Houston, Texas, United States

The Don and Sybil Harrington Cancer Center; 🇺🇸 Amarillo, Texas, United States

University of Texas Medical Branch; 🇺🇸 Galveston, Texas, United States

Sentara Martha Jefferson Hospital; 🇺🇸 Charlottesville, Virginia, United States

Northwest NCI Community Oncology Research Program; 🇺🇸 Tacoma, Washington, United States

University of Wisconsin Hospital and Clinics; 🇺🇸 Madison, Wisconsin, United States

Saskatoon Cancer Centre; 🇨🇦 Saskatoon, Saskatchewan, Canada

Instituto Nacional de Enfermedades Neoplasicas; 🇵🇪 Lima, Peru

Froedtert and the Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

University Of Pretoria; 🇿🇦 Pretoria, South Africa

Michigan Cancer Research Consortium NCORP; 🇺🇸 Ann Arbor, Michigan, United States

University of Michigan Comprehensive Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

AdventHealth Orlando; 🇺🇸 Orlando, Florida, United States

Memorial Hospital of Rhode Island; 🇺🇸 Pawtucket, Rhode Island, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Roper Hospital; 🇺🇸 Charleston, South Carolina, United States

UNC Lineberger Comprehensive Cancer Center; 🇺🇸 Chapel Hill, North Carolina, United States

Southwestern Vermont Medical Center; 🇺🇸 Bennington, Vermont, United States

University of Oregon; 🇺🇸 Eugene, Oregon, United States

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States